On-DNA Decarboxylative Arylation: Merging Photoredox with Nickel Catalysis in Water

Abstract

A new catalytic manifold that merges photoredox with nickel catalysis in aqueous solution is presented. Specifically, the combination of a highly active, yet air-stable, nickel precatalyst with a new electron-deficient pyridyl carboxamidine ligand was key to the development of a water-compatible nickel catalysis platform, which is a crucial requirement for the preparation of DNA-encoded libraries (DELs). Together with an iridium-based photocatalyst and a powerful light source, this dual catalysis approach enabled the efficient decarboxylative arylation of α-amino acids with DNA-tagged aryl halides. This C(sp 2 )−C(sp 3 ) coupling tolerates a wide variety of functional groups on both the amino acid and the aryl halide substrates. Due to the mild and DNA-compatible reaction conditions, the presented transformation holds great potential for the construction of DELs. This was further evidenced by showing that well plate-compatible LED arrays can serve as competent light sources to facilitate parallel synthesis. Lastly, we demonstrate that this procedure can serve as a blueprint toward the adaptation of other established nickel metallaphotoredox transformations to the idiosyncratic requirements of a DEL.

RASS‐Enabled S/P−C and S−N Bond Formation for DEL Synthesis

“…As a result, few conditions for the creation of on‐DNA C−S bonds, including sulfones and sulfides, have been reported. Low valent nickel has been proven to be a powerful mediator of multiple cross‐coupling reactions and its utility has been recently realized and exploited in the DEL field …”

DNA Encoded Libraries: A Visitor's Guide

“…The broad scope of this transformation, its use of ubiquitous carboxylic acid building blocks, and its demonstration on‐DNA bode well for its use in DEL and encourage the development of other radical based transformations . The Molander group, as well as the Flanagan group, also reported the use of radical chemistry in a DEL‐context using photoinduced electron transfer to couple amino acids or other radical precursors (dihydropyridines, silicates) to aromatic systems . The useful C(sp 2 )‐C(sp 3 ) linkages contained in the structures generated were previously outside the realm of DEL‐based chemistry.…”

Recent Advances in Photocatalytic Decarboxylative Coupling Reactions in Medicinal Chemistry

“…Since 2018, Kölmel, Flanagan, and co-workers have successfully extended this dual catalytic process to the decarboxylative arylation of DNA-tagged aryl halides and N-Boc--amino acids, 31,32 a transformation of particular importance in the preparation of DNA-encoded libraries (DELs). DELs have recently established themselves as a powerful hit finding technique currently employed by many drug dis-covery companies, enabling access to much wider chemical space than previously accessible through classical highthroughput screening alone.…”